The overall goal of our group is to halt the type 2 diabetes epidemic by finding a cure for this disease. To achieve this ambitious goal we need to understand genetic and non-genetic causes of type 2 diabetes. A key resource in these attempts is the Botnia Study.

Groop group

Groop

Genomics of Type 2 Diabetes and Related Disorders

Background

Diabetes mellitus is a lifelong, incapacitating disease affecting multiple organs. Worldwide prevalence figures estimate that there are 350 million diabetic patients in 2013 and more than 550 million in 2030. In Finland, 320.000 people received anti-diabetic treatment in 2011, but the number of individuals with undiagnosed diabetes might increase the number to 500,000 people; of them about 90% has type 2 diabetes (T2D), thereby making T2D to the fastest increasing disease in Finland and worldwide. This epidemic has been ascribed to a collision between genes and the environment, but dissection of the genomics of T2D will not only benefit from the rapid development of sequencing tools but will also require a much better phenotyping of diabetic subgroups than hitherto applied .

The classical subdivision of diabetes into Type 1 diabetes (T1D) and T2D is an oversimplification and it is rather likely that they represent the extremes of a continuum with T1D with insulin deficiency due to autoimmune causes on one end and T2D with metabolic syndrome on the other. About 15 years ago we described another form of diabetes, LADA (Latent Autoimmune Diabetes in Adults) which seems to represent an admixture of the two main forms of diabetes.

Research Strategy

The overall goal is to halt the epidemic by finding a cure for T2D. To achieve this ambitious goal we need to understand genetic and non-genetic causes of T2D and be able to distinguish it from other forms of diabetes. A key resource in these attempts is the Botnia Study.

The Botnia Study

The Botnia Study was initiated 1990 on the Western Coast of Finland near the Gulf of Bothnia. The study includes information on 25962 individuals from 1131 families. In addition, the Botnia Prospective Study (BPS) includes 2700 persons followed for 10 years, 300 of whom developed T2D. The population-based PPP-study( Prevalence Prediction Prevention of T2D) includes 5200 individuals aged 18-75 yrs with a 5-year follow-up carried out in more than 3000 persons.. The DIREVA (Diabetes Registry Vaasa) currently includes more than 4,500 patients from the region but is predicted to include most patients including information on disease progression, complications and treatment.

The aims of the Botnia Study are:

- Describe the metabolic disturbances leading to T2D

- Identify the genetic causes of T2D

- Use this information to predict the disease

- Use this information to prevent the disease

The Botnia study includes information on 25962 individuals from 1131 families. In addition, the Botnia Prospective Study (BPS) includes 2700 persons followed for 10 years, 150 of whom developed T2D. The population-based PPP-study includes 5200 individuals aged 18-75 yrs. The DIREVA (Diabetes Registry Vaasa) currently includes 4,500 patients but is predicted to include 10,000 well characterized patients in 2014.

Projects

We have over the years demonstrated linkage to T2D and several chromosomal regions in families from the Botnia study, e.g.linkage to chromosome 12 in families with impaired insulin secretion (16), to chromosome 9 in families with T2D (17) and to chromosome 18 in obese T2D individuals (18). The rapid development of next generation sequencing tools should make this possible.

Exome sequencing of families with extremes of quantitative traits

From studies on lipids it has been shown that exome sequencing is an efficient tool to identify less frequent variants with stronger effects on the trait. In the Botnia study we have calculated family means of a number of metabolic traits (insulin secretion and action, lipids, FFA, measures of body composition). We will now select extremes of these traits defined as highest and lowest decentile of the trait for sequencing.

T2D is more common in offspring of diabetic mothers than fathers (2) and several studies have shown increased risk of T2D if the risk allele is transmitted from the mother rather than from the father (12,13, 27). Children with low birth weight have an increased risk to develop T2D later in life (14), a phenomenon which has been ascribed to intrauterine programming (14,28). This could include imprinting of genes important for β-cell development and mass. The most likely mechanism for imprinting would be silencing of a gene through DNA methylation. In general, diabetes develops when people no longer can increase their insulin secretion capacity to meet increased demands imposed by obesity and insulin resistance (8). The hypothesis can therefore be advanced that intrauterine imprinting of key genes for β-cell development will result in reduced β-cell mass and make these people more susceptible to develop T2D later in life. Studies of parent-of-origin specific transmissions have been hampered by the paucity of family trios, i.e. pedigrees with DNA from both parents and offspring (29). The Botnia study provides a rich resource of trios which can be further enlarged by searching for so called “surrogate parents” by taking advantage of the isolated nature of the region and that people share long stretches of the chromosomes (haplotypes).

Describing the spectrum of diabetic subgroups

It can be assumed that a better classification of diabetes into subgroups may aid in better individualized treatment. The current subdivision into T1D and T2D most likely reflects an oversimplification of the situation where T1D and T2D represent extreme forms at the ends of the spectrum with insulin deficiency and autoimmunity dominating for T1D and insulin resistance and features of the metabolic syndrome for T2D. In the middle is LADA (Latent Autoimmune Diabetes in Adults), a common form of diabetes with features of both T1D and T2D. In an attempt to provide a better characterization of diabetes we initiated the DIREVA project (Diabetes Registry Vaasa) in 2010, a registry of all known diabetic patients in the Vaasa Central Hospital Region . The registry currently includes more than 4,500 patients but is predicted to include 10,000 well characterized patients at the end of 2015. For the purpose of better diabetes classification we will combine genetic and non-genetic (biomarkers, metabolites, circulating miRNAs) with information from the hospital discharge records and the Drug Prescription Registry. This will allow us to use baseline information to predict progression of the disease, development of complications and response to or side effects from treatment.

Last updated: 03.01.2017 - 13:42

Leif Groop

Leif Groop, M.D., Ph.D. is since 1993 Professor in Endocrinology at Lund University and Director of Lund University Diabetes Centre. He is also Academy of Finland Finnish Distinguished Professor (FiDiPro) at the Institute for Molecular Medicine Finland (FIMM). He received his MD at University of Berne, Switzerland and PhD at University of Helsinki, Finland. After a PostDoc period at Yale University he devoted his research to dissection of the heterogeneity of diabetes but also to explore the pathogenic events leading to type 2 diabetes. As an important tool to achieve this goal, he initiated the Botnia Study at the west coast of Finland, one of the world's largest family studies on type 2 diabetes.
The research group has been involved in many of the genetic discoveries on type 2 diabetes during the past 15 years, including one of the first whole genome association studies for type 2 diabetes. He is a member of the Swedish Royal Academy of Science, he has served on numerous editorial boards and achieved several international recognitions, including the Claude Bernard, Anders Jahre, Fernströms and Söderberg awards.

Contacts

Sari Kivikko

Project Coordinator

+358 40 567 0826

Group members

Show information

Close

Om Dwivedi

Post-doctoral Researcher

Show information

Om Dwivedi

Post-doctoral Researcher

+358 50 448 5363

Close

Harry Holthöfer

Research Director

Show information

Harry Holthöfer

Research Director

Close

Mikko Lehtovirta

Post-doctoral Researcher

Show information

Mikko Lehtovirta

Post-doctoral Researcher

+358 50 517 1938

Close

Tiinamaija Tuomi

Senior Researcher

Show information

Tiinamaija Tuomi

Senior Researcher

+358 50 427 9013

Close

Our research is funded by:

FIMM

P.O. Box 20
FI-00014 University of Helsinki
FINLAND

Social Media

About FIMM

The mission of the Institute is to advance new fundamental understanding of the molecular, cellular and etiological basis of human diseases. This understanding will lead to improved means of diagnostics and the treatment and prevention of common health problems. Finnish clinical and epidemiological study materials will be used in the research. Learn more about FIMM.